More than five million Americans are living with Alzheimer’s disease (AD). Of them, 400,000 also have Down syndrome. People with Down syndrome (DS) represent the world’s largest population of predetermined Alzheimer’s disease. It is hoped that by studying these individuals, researchers can develop insights into how Alzheimer’s disease naturally progresses.  Both groups of patients have similar looking brains with higher levels of the protein beta amyloid. In fact, patients with Down syndrome develop the abnormal protein at twice the rate.

Now, a pilot study from researchers at UC San Diego has validated the pathogenic role of beta amyloid in dementia as seen in both AD and Down syndrome.  The opensource study is published in the journal Frontiers in Behavioral Neuroscience.

Previous studies suggest that AD biomarker changes in DS are similar to those observed in familial and sporadic AD. Studies demonstrate a six-fold increase in plasma Aβ in individuals with DS as compared to age-matched non-DS individuals and Aβ positron emission tomography (PET) imaging data in DS are consistent with AD patients. Furthermore, as seen in familial and sporadic AD, the presence of the Apolipoprotein E (ApoE) ε4 allele is generally associated with greater accumulation of Aβ plaques in the brains of adults with DS. The presence of ApoE ε4 allele is also associated with an earlier age of onset of dementia.

AD is believed to occur from the toxic buildup of beta amyloid. There are many forms of AD that are genetically inherited, including Down syndrome. People with Down syndrome have an extra copy of the 21st chromosome where the production gene for the beta amyloid protein resides.  Postmortem studies indicate that adults with DS have a similar, prominent pattern of cerebral atrophy involving the medial temporal lobe structures, as seen in the early stages of AD.  Therefore, the group state that the ultimate aim of their work is to aid the development of preventive therapies for the dementia associated with both DS and AD, based on the apparent common pathogenic role of beta amyloid (Aβ) in the two conditions.

The current study is called the Down Syndrome Biomarker Initiative (DSBI), a 3-year study involving twelve participants between the ages of 30 and 60 with Down syndrome. The team focused on how soon protein plaques developed, where in the brain they’re located and the effects of the plaques on cognition. To quantify how much amyloid was present in the brain, the study included extensive neuroimaging such as volumetric MRI, amyloid PET, FDG PET, and retinal amyloid imaging.

Data findings show that of the 12 subjects, 50% were ApoE4 carriers and all of the ApoE4 non-carriers were female, while four of the ApoE4 carriers were female.  The the team note that this could be due to the fact that the trial contained 10 female participants compared to 2 male participants.  These two groups did not differ significantly in psychological test scores even though neuroimaging showed that all subjects were amyloid positive to varying degrees.  Results also show that prior to dementia onset, changes in volumetric MRI, amyloid PET and FDG PET and plasma are detectable and consistent with preclinical AD in adults with DS.

The team surmise that their findings show some of the earliest known Alzheimer’s disease biomarker changes in adults with Down syndrome and underscores the need for additional studies.  The team conclude that this study will set the stage for the first clinical trial of anti-beta amyloid therapy in the preclinical treatment of Alzheimer’s disease in adults with Down syndrome.  For the future the lab is continuing to characterize the age-related trajectory of biomarker changes associated with preclinical AD to set the stage for the first clinical trial of an anti-Aβ therapy in the preclinical treatment of AD in adults with DS.

Source: UC San Diego Health